Palladium

Endpoint summary

Description of key information

Palladium metal is likely to be poorly absorbed after administration by the oral route, based on a low water solubility and a lack of appreciable bio-elution in simulated gastric fluid; what small proportion of the substance is taken up is likely to be rapidly excreted. As such, predicted oral absorption of palladium is set at 10%.

Although not expected to reach the lungs in appreciable quantities (based on respiratory tract deposition modelling data), as a relatively low molecular weight substance, any palladium reaching the lungs has the potential to be absorbed through aqueous pores. As such, the predicted inhalation absorption is conservatively set at 100%.

Palladium’s low water solubility (<0.1 mg/L) means that it may not undergo appreciable uptake by the dermal route, especially considering the low dermal penetration expected for metals. Moreover, palladium lacks skin irritation potential (which could, in theory, disrupt skin barrier function). As such, predicted dermal absorption is conservatively set at 10%.

Once absorbed, distribution and excretion of palladium ions are expected to be rapid, with little or no bioaccumulation occurring. The potential for bioaccumulation of certain other metals and ions is recognised.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Absorption

Good-quality information on absorption of palladium compounds is very limited. In general, a substance needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration. Experts from the IPCS reported that absorption of palladium ions from the gastrointestinal tract is poor, a view based on a study where adult and suckling rats absorbed less than 0.5% and about 5%, respectively, of a single oral dose of radiolabelled (103Pd) palladium dichloride (IPCS, 2002). Experts from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) used an oral absorption figure of 10% when converting an oral permitted daily exposure figure for palladium compounds to a parenteral equivalent (ICH, 2014). While palladium is essentially insoluble in water (<0.1 mg/L; Skeaff, 2011), in bio-elution tests with palladium powder, the proportion of metal release (from total metal content) in simulated gastric fluid was 0.32% after 2 hours. This indicates a limited potential for oral availability of the metal (as cations). Considering expert ECHA guidance, the low molecular weight (~106 g/mol i.e. less than 200 g/mol) means that the ions may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Nevertheless, the absorption of palladium (as palladium ions) from the gastro-intestinal tract is anticipated to be limited. As such, predicted oral absorption of palladium is set at 10%.

No good-quality data were found regarding absorption of palladium compounds following inhalation. One Expert Group noted that, following a single intratracheal or inhalation (7.2 mg/m3; aerodynamic diameter around 1 µm) exposure to 103Pd-radiolabeled palladium dichloride in rats, absorption/retention was higher than was observed for oral administration (i.e. >5%) but did not differentiate between absorption and mere retention in the respiratory tract. Six months after a single intratracheal application of 50 mg palladium dust (mass median aerodynamic diameter 3.92 µm) to rats, palladium particles were found to be localized intracellularly in alveolar macrophages (IPCS, 2002). Vapour pressure testing was waived on the basis of palladium having a high melting point (1555°C; Lide, 2008). Particle size distribution (PSD) data indicates that a significant proportion of palladium metal is <100 μm, based on average 10th, 50th and 90th percentile particle sizes of 34, 52 and 79 μm, respectively, for palladium powder (Potthoff, 2012). Moreover, dustiness testing, a more energetic PSD measurement, with the metal returned a mass median aerodynamic diameter (MMAD) value of 30.2 μm (Selck and Parr, 2012). An MMAD value <100 μm indicates that a significant proportion of a substance is likely to be inhalable. Nevertheless, respiratory tract deposition modelling with the dustiness data yielded output values of 45.8, 0.12 and 0.08% for the nasopharyngeal (head), tracheobronchial (TB) and pulmonary regions of the respiratory tract, respectively. Hence, very little airborne substance (0.2%) is expected to deposit in the lower regions of the human respiratory tract, i.e. the TB or pulmonary regions via oronasal normal augmenter breathing.

Most of the inhaled fraction is likely to be retained in the head region and, based on a low water solubility (<0.1 mg/L), could be coughed or sneezed out of the body or swallowed, with systemic uptake being determined predominantly by subsequent oral bioavailability. The insoluble nature of the substance would limit any diffusion/dissolution into the mucus lining the respiratory tract. However, any palladium which is able to migrate into the mucus has the potential to be absorbed directly across the respiratory tract epithelium by passive diffusion. At most only <1% of the inhaled fraction is capable of reaching the alveoli. Thus, absorption via the lungs will not be a significant route of exposure. Any palladium reaching the lungs would mainly be engulfed by alveolar macrophages and translocated out of the respiratory tract by absorption. Overall, while it is very unlikely that palladium will be available to a high extent via inhalation, it is considered health precautionary in the light of the lack of specific absorption data, to take forward the ECHA default inhalation absorption value of 100%.

No good-quality data were found regarding absorption following dermal exposure to palladium compounds. One Expert Group noted that “palladium was found in all internal organs examined” after dermal treatment of rabbits with “palladium hydrochloride” (formula not specified) or guinea pigs with chloropalladosamine, but quantitative absorption data were not given (IPCS, 2002). Estimation of dermal absorption is based on relevant available information (mainly water solubility, molecular weight and log Pow) and expert judgement. Partition coefficient testing was waived on the basis of the inorganic nature of substance. Given the insoluble nature of palladium (<0.1 mg/L), dermal uptake is likely to be low. In spite of this, in the light of the limited available experimental data, ECHA guidance indicates that a default value of 100% dermal absorption should be used (ECHA, 2014). Nevertheless, specific guidance on the health risk assessment of metals indicates that molecular weight and log Pow considerations do not apply to these substances (“as inorganic compounds require dissolution involving dissociation to metal cations prior to being able to penetrate skin by diffusive mechanisms”) and tentatively proposes dermal absorption figures: 1.0 and 0.1% following exposure to liquid/wet media and dry (dust) respectively (ICMM, 2007). Further, palladium is not classified for skin irritation. This is based on the lack of irritation potential observed in guinea pigs (Arcelin, 1992). Moreover, in bio-elution tests with the two forms of the metal, the proportion of metal release (from total metal content) in simulated dermal fluid was 0.003% after both 24 and 168 hours for palladium powder (Rodriguez, 2012), indicating a low dermal bioavailability of the compound. Given the low penetration expected for metals, and the low water solubility (and, thus, low expected dermal bioavailability), it is suitably health precautionary to take forward the lower of the two ECHA default values for dermal absorption, of 10%, for the safety assessment of palladium.

No overt systemic toxicity was seen in the existing in vivo skin irritation/sensitisation study on palladium (Arcelin, 1992), providing limited evidence that it may not be well-absorbed dermally.

Distribution/Metabolism

Once absorbed, distribution of palladium ions (the anticipated form of the metal in vivo) throughout the body is expected based on water solubility of the cationic form (and a relatively low molecular weight).

Insight into the distribution of absorbed palladium can be obtained from a study on dipotassium hexachloropalladate. This salt is water soluble (3.41 g/L); while palladium metal is essentially insoluble in aqueous media, in gastric fluid limited bioavailability would be expected. When rats were given potassium hexachloropalladate in the drinking water at 0, 10, 100 or 250 mg/L for 90 days, absorbed Pd was found mainly in the kidneys; no significant amounts of palladium were detected in the liver, lung, spleen or bone tissue (Iavicoli et al., 2010). IPCS noted that, after single oral, intravenous or intratracheal doses of palladium salts or complexes to rats, rabbits or dogs, the highest palladium concentrations were found in kidney, liver, spleen, lymph nodes, adrenal gland, lung and bone (IPCS, 2002).

Elimination

In rats given potassium hexachloropalladate in the drinking water at up to 250 mg/L for 90 days, elimination was rapid and primarily through the faecal route. A linear correlation between the administered dose and faecally-excreted levels was observed; the high concentration of Pd detected in the faeces was postulated to be a result of non-absorption. Small amounts of palladium were detected in the urine at the highest dose level (Iavicoli et al., 2010).

Palladium displayed poor water solubility, while bio-elution test data indicate a lack of appreciable release of the metal (to ionic form) in simulated gastric fluid. Rapid excretion of any absorbed palladium is likely based on the low molecular weight. It is noted that certain metals and ions may interact with the matrix of the bone, causing them to accumulate within the body (ECHA, 2014). However, any absorbed palladium will likely be in the form of palladium ions, and the potential for bioaccumulation is considered to be low, based on a low anticipated affinity for the lipophilic tissues.

Conclusion

Based on the physico-chemical properties, the chemical structure, molecular weight and the results of toxicity and bio-elution studies, as well as limited toxicokinetic data on other palladium compounds, palladium is likely partially bioavailable by the oral route and rapidly excreted once absorbed. A high dermal bioavailability is unlikely, particularly as the substance is an inorganic solid with a lack of skin irritation potential and unfavourable bio-elution parameters. Although bioavailability by the inhalation route is anticipated to be low (based on respiratory tract deposition modelling data), inhalation absorption is considered a possibility based on its low molecular weight. Proposed predicted absorption figures for the oral, dermal and inhalation routes are 10, 10 and 100%, respectively.

 

References not included elsewhere:

ECHA (2014). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.7c: endpoint specific guidance. Version 2.0. November 2014.

Iavicoli I, Bocca B, Fontana L, Caimi S, Bergamaschi A and Alimonti A (2010). Distribution and elimination of palladium in rats after 90-day oral administration. Toxicology and Industrial Health 26, 183-189.

ICH (2014). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Guideline. Guideline for elemental impurities. Q3D Current Step 4 version dated 16 December 2014.

ICMM (2007). International Council on Mining & Metals. Health risk assessment guidance for metals. September 2007.

IPCS (2002). International Programme on Chemical Safety. Palladium. Environmental Health Criteria 226. WHO, Geneva.